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Abstract Hypoxia is a common feature of glioblastoma (GBM). Circular RNAs (circRNAs) are identified as regulators in cancers. However, the role of circRNAs in GBM remains elusive. Here, circPLOD2a and circPLOD2b, spliced from the same parental gene PLOD2, are identified as hypoxia-responsive circRNAs. Overexpression of circPLOD2a and b enhance while knockdown inhibit GBM cell aggressiveness. The protein partners and downstream molecules were investigated by RNA-pulldown, mass spectrometry and RNA-seq. Mechanistically, HIF1α induces the expression of circPLOD2a and b, which competitively bind to HuR, causing a degradation of XIRP1 in vitro and in vivo. Clinical data demonstrate circPLOD2a and b are highly expressed in GBM negatively correlated with XIRP1, whose lower expression associates with higher glioma grade and worse prognosis. In conclusion, hypoxia-induced circPLOD2a and b are oncogenic regulators of tumour aggressiveness through attenuating the interaction between HuR and XIRP1 in glioblastoma cells and may be potential therapeutic targets for this disease.

Cerebral cavernous malformation (CCM) is a polygenic disease with intricate genetic interactions contributing to quantitative pathogenesis across multiple factors. The principal pathogenic genes of CCM, specifically KRIT1, CCM2, and PDCD10, have been reported, accompanied by a growing wealth of genetic data related to mutations. Furthermore, numerous other molecules associated with CCM have been unearthed. However, tackling such massive volumes of unstructured data remains challenging until the advent of advanced large language models. In this study, we developed an automated analytical pipeline specialized in single nucleotide variants (SNVs) related biomedical text analysis called BRLM. To facilitate this, BioBERT was employed to vectorize the rich information of SNVs, while a deep residue network was used to discriminate the classes of the SNVs. BRLM was initially constructed on mutations from 12 different types of TCGA cancers, achieving an accuracy exceeding 99%. It was further examined for CCM mutations in familial sequencing data analysis, highlighting an upstream master regulator gene fibroblast growth factor 1 (FGF1). With multi-omics characterization and validation in biological function, FGF1 demonstrated to play a significant role in the development of CCMs, which proved the effectiveness of our model. The BRLM web server is available at http://1.117.230.196.

Incomplete elevational sampling in studies of biodiversity and community assembly along elevational gradients can result in inconsistent findings and potentially inaccurate conclusions about assembly mechanisms. In this study, we conducted extensive sampling of small mammals over a 3200 m elevational gradient on Xiling Snow Mountain, Southwestern China. We integrated functional and phylogenetic diversity to determine the mechanisms structuring small mammal assemblages. Our findings indicate that taxonomic, functional, and phylogenetic diversity, along with all species richness-corrected indices of functional and phylogenetic diversity, exhibit similar hump-shaped patterns. Our results suggest that environmental filtering plays a considerable role in structuring small mammal communities at low and high elevations, while competitive exclusion governs the assembly processes at middle elevations. Human footprint, Normalized Difference Vegetation Index, precipitation seasonality and potential evapotranspiration are key drivers of small mammal diversity and community structure along elevational gradients. In summary, our study provides evidence that phylogenetic diversity is a robust surrogate for functional diversity, and challenges the recent large-scale studies that advocate a linear relationship between small mammal assembly process and elevation. We emphasize the importance of continuously documenting general patterns of small mammal diversity across entire elevational gradients in future studies.

Abstract Temozolomide (TMZ) resistance is a major challenge in the treatment of glioblastoma (GBM). Tumour reproductive cells (TRCs) have been implicated in the development of chemotherapy resistance. By culturing DBTRG cells in three-dimensional soft fibrin gels to enrich GBM TRCs and performing RNA-seq analysis, the expression of stanniocalcin-1 (STC), a gene encoding a secreted glycoprotein, was found to be upregulated in TRCs. Meanwhile, the viability of TMZ-treated TRC cells was significantly higher than that of TMZ-treated 2D cells. Analysis of clinical data from CGGA (Chinese Glioma Genome Atlas) database showed that high expression of STC1 was closely associated with poor prognosis, glioma grade and resistance to TMZ treatment, suggesting that STC1 may be involved in TMZ drug resistance. The expression of STC1 in tissues and cells was examined, as well as the effect of STC1 on GBM cell proliferation and TMZ-induced DNA damage. The results showed that overexpression of STC1 promoted and knockdown of STC1 inhibited TMZ-induced DNA damage. These results were validated in an intracranial tumour model. These data revealed that STC1 exerts regulatory functions on MGMT expression in GBM, and provides a rationale for targeting STC1 to overcome TMZ resistance.

Abstract Background 'Taishuu' has a crisp texture, abundant juice, and sweet flavor with hints of cantaloupe. The availability of mitochondrial genome data of Diospyros species is far from the known number of species. Results The sequencing data were assembled into a closed circular mitochondrial chromosome with a 421,308 bp length and a 45.79% GC content. The mitochondrial genome comprised 40 protein-coding, 24 tRNA, and three rRNA genes. The most common codons for arginine (Arg), proline (Pro), glycine (Gly), tryptophan (Trp), valine (Val), alanine (Ala), and leucine (Leu) were AGA, CCA, GGA, UGG, GUA, GCA, and CUA, respectively. The start codon for cox1 and nad4L protein-coding genes was ACG (ATG), whereas the remaining protein-coding genes started with ATG. There are four types of stop codons: CGA, TAA, TAG, and TGA, with TAA being the most frequently used stop codon (45.24%). In the D. kaki Thunb. 'Taishuu' mitochondrial genome, a total of 645 repeat sequences were identified, including 125 SSRs, 7 tandem repeats, and 513 dispersed repeats. Collinearity analysis revealed a close relationship between D. kaki Thunb. 'Taishuu' and Diospyros oleifera, with conserved homologous gene fragments shared among these species in large regions of the mitochondrial genome. The protein-coding genes ccmB and nad4L were observed to undergo positive selection. Analysis of homologous sequences between chloroplasts and mitochondria identified 28 homologous segments, with a total length of 24,075 bp, accounting for 5.71% of the mitochondrial genome. These homologous segments contain 8 annotated genes, including 6 tRNA genes and 2 protein-coding genes (rrn18 and ccmC). There are 23 homologous genes between chloroplasts and nuclei. Mitochondria, chloroplasts, and nuclei share two homologous genes, which are trnV-GAC and trnW-CCA. Conclusion In conclusion, a high-quality chromosome-level draft genome for D. kaki was generated in this study, which will contribute to further studies of major economic traits in the genus Diospyros.

Abstract Glioblastoma multiforme (GBM) is a complex disease to treat owing to its profound chemoresistance. Therefore, we evaluated the combined effect and therapeutic efficacy of temozolomide (TMZ), a potent alkylating agent and the current gold standard therapy for GBM, and cryptotanshinone (CTS), which inhibits glioma cell proliferation in GBM cells. Using LN229 and U87-MG human GBM cells in a short-term stimulation in vitro model, the cytotoxic and anti-proliferative effects of single and combined treatment with 4 μM CTS and 200 μM TMZ were investigated. Furthermore, cell viability, DNA damage, apoptosis rate, and signal transducer and activator of transcription 3 (STAT3) protein were measured using cytotoxic assay, comet assay, flow cytometry, and western blotting analysis, respectively. The two drugs’ synergistic interaction was validated using the synergy score. We found that the anti-proliferative effects of combination therapy using the two drugs were greater than that of each agent used alone (CTS or TMZ). Western blot analysis indicated that treatment of GBM cells with CTS combined with TMZ more significantly decreased the expression of MGMT and STAT3, than that with TMZ alone. Combined treatment with CTS and TMZ might be an effective option to overcome the chemoresistance of GBM cells in a long-term treatment strategy.

Abstract Background The aim of this study was to review clinical features of adolescent malignant germ cell tumors (MGCTs) in Beijing and analyze the peculiar characteristics of this age group. Methods Clinical characteristics, pathological presentations, and survival outcomes of 34 patients were analyzed retrospectively. Results Of 34 patients, 12 girls and 22 boys, 18 (52.9%) had an extra‐cranial tumor, including one testicular tumor, five ovarian tumors, one sacrococcygeal tumor, and 11 mediastinal tumors. Histologically, we found immature teratomas (n = 6), yolk sac tumors (n = 5), mixed malignant tumors (n = 5), an embryonic carcinoma (n = 1), and seminoma (n = 1). Three‐year event‐free survival (EFS) and overall survival (OS) were 48.8% and 62.9%, respectively. Another 16 (47.1%) patients had an intracranial tumor, including nine in the pineal region, five in the suprasellar region, one in basal ganglia, and one in cerebellopontine. All patients had localized disease and an excellent outcome with 3‐year EFS and OS of 93.7% and 100%, respectively. Conclusions Adolescent MGCTs are rare with a strong dependence on gender, and the mediastina and pineal region are the most common tumor locations. The prognosis is promising compared with that of other adolescent tumors and MGCTs in other age groups. MGCTs in mediastina have a tendency to companion with other hematological malignancies, and the prognosis is extremely poor in these patients.

Abstract We report two children with hepatoblastoma (HB) with a history of neonatal necrotizing enterocolitis (NEC). Case 1 was diagnosed with HB at 5 months of age. Liver enlargement was found during the NEC operation at 3 months of age and then was clinically diagnosed by imaging. After six chemotherapy courses, a partial hepatectomy was performed. Three months after ceasing the chemotherapy, a chest computed tomography scan suggested that distant metastasis of the tumor should be considered, and the lesion was removed. However, 9 months after the operation, alpha‐fetoprotein concentrations were increased, and abdominal imaging showed a recurrence of the tumor in situ, resulting in a hepatectomy. Case 2 was diagnosed with NEC shortly after birth and underwent an intestinal resection and anastomosis 1 month later. He was diagnosed with HB at 3 years of age. Hepatectomy was performed after five courses of chemotherapy. Chemotherapy was stopped after 10 courses, and alpha‐fetoprotein concentrations were normal. At present, both children have survived and are in a healthy condition. Physicians should be aware of the possibility of HB and a history of NEC in children. Premature birth and low birth weight are common factors leading to the pathogenesis of HB and NEC. The association between these two diseases requires further study.

Abstract Multiple primary lung cancers (MPLCs) pose diagnostic and therapeutic challenges in clinic. Here, we orchestrated the cellular and spatial architecture of MPLCs by combining single-cell RNA-sequencing and spatial transcriptomics. Notably, we identified a previously undescribed sub-population of epithelial cells termed as CLDN2 + alveolar type II (AT2) which was specifically enriched in MPLCs. This subtype was observed to possess a relatively stationary state, play a critical role in cellular communication, aggregate spatially in tumor tissues, and dominate the malignant histopathological patterns. The CLDN2 protein expression can help distinguish MPLCs from intrapulmonary metastasis and solitary lung cancer. Moreover, a cell surface receptor−TNFRSF18/GITR was highly expressed in T cells of MPLCs, suggesting TNFRSF18 as one potential immunotherapeutic target in MPLCs. Meanwhile, high inter-lesion heterogeneity was observed in MPLCs. These findings will provide insights into diagnostic biomarkers and therapeutic targets and advance our understanding of the cellular and spatial architecture of MPLCs.

Abstract Rhabdomyosarcomas (RMSs) are highly malignant soft‐tissue sarcomas. Head and neck RMSs often pose unique challenges to treatment because of their closeness to important structures. We here report a rare case of a 1‐year‐old boy with a 1‐month history of right eye swelling and an eye mass. Biopsy of deep tumors in the maxillofacial region supports embryonal RMS. Postoperative positron emission computed tomography showed a 5.0 cm × 4.8 cm × 4.2 cm malignant tumor in the right maxillary region. In accordance with the international RMS study group guideline, the child was diagnosed with IIIa and TNM stage T2bN1M1 embryonal RMS. The child was treated with a combination of chemotherapy and 125I seed implantation radiotherapy and eventually achieved partial remission. This case report shows that 125I seed implantation is a safe and effective means of delivering radiotherapy to young children with head and neck RMSs. It may be an option for children with RMSs for whom surgery or external radiotherapy is unsuitable.

Titanium dioxide (TiO2) composites are popular photocatalysts for hydrogen production from water. Here we report a composite consisting of S and N co-doped graphene quantum dots (SN-GQDs) with (001)TiO2 for photocatalytic hydrogen production. In addition to traditional advantages like light absorption promotion and charge transfer improvement, the as-prepared SN-GQDs/(001)TiO2 composite could significantly enhance the surface reaction by promotion of the formation of hydroxyl radicals, which results in the increase of the hydrogen production activity by 40 times. This work reveals the importance of surface reaction promotion by GQDs for hydrogen production, which will help researchers understand relevant systems comprehensively.

Abstract The developmental transcriptomes of Sarcomyxa edulis were assessed to explore the molecular mechanisms underlying lignocellulose degradation. Six stages were analyzed, spanning the entire developmental process: growth of mycelium until occupying half the bag (B1), mycelium under low-temperature stimulation after occupying the entire bag (B2), appearance of mycelium in primordia (B3), primordia (B4), mycelium at the harvest stage (B5), and mature fruiting body (B6). Samples from all six developmental stages were used for transcriptome sequencing, with three biological replicates for all experiments. A co-expression network of weighted genes associated with extracellular enzyme physiological traits was constructed using weighted gene co-expression network analysis (WGCNA). We obtained 19 gene co-expression modules significantly associated with lignocellulose degradation. In addition, 12 key genes and 8 kinds of TF families involved in lignocellulose degradation pathways were discovered from the four modules that exhibited the highest correlation with the target traits. These results provide new insights that advance our understanding of the molecular genetic mechanisms of lignocellulose degradation in S. edulis to facilitate its utilization by the edible mushroom industry.

The construction of micro/nanohierarchical structures on cellulose-based materials to prepare membranes with special wettability has a promising application. Herein, a simple two-step preparation process, including immersion of the cotton fabric in the copper ammonia solution and drying, was used to grow copper hydroxide (Cu(OH)2) on/in the cotton fibers in a homogeneous reaction, avoiding severe agglomeration of Cu(OH)2 particles and endowing the fabric with superhydrophilicity and underwater superoleophobicity. Driven by gravity, the prepared Cu(OH)2@cotton fabric could be used to separate different oil-water mixtures and oil-in-water emulsions as well as having good mechanical and chemical stability. This simple, low-cost, mass-applicable method offers new perspectives for designing the membrane with special wettability based on cotton fabrics, with promising applications.

Owing to messenger RNA's unique biological advantages, it has received increasing attention to be used as a therapeutic, known as mRNA-based gene therapy. It is critical to have an ideal strategy of mRNA gene therapy for glioma, which grows in a special environment. In the present study, we screened out a safe and efficient transfection reagent for intracranial delivery of synthetic mRNA in mouse brain. First, in order to analyze the effect of different transfection reagents on the intracranial delivery of mRNA, the synthetic luciferase mRNA was wrapped with two different transfection reagents and microinjected into the brain at the fixed point. The expression status of delivered mRNA was monitored by a small animal imaging system. The possible reagent-induced biological toxicity was evaluated by behavioral and blood biochemical measurements. Then, to test the therapeutic effect of our intracranial delivery mRNA model on glioma, synthetic modified tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mRNA was used as an example of therapeutic application. This model demonstrated that synthetic mRNA could be successfully delivered into the brain using commercially available transfection reagents, and TransIT-mRNA showed better results than in vivo-jetPEI kit. This model can be applied in precise targeting and personalized gene therapy of glioma.

Ramie fabrics are suitable for summer clothing due to their excellent moisture absorption and breathability. Still, their application in the garment industry is limited by the presence of stiff, coarse hairiness that tends to prickle when it comes into contact with the skin. Herein, a low concentration copper ammonia solution was used to slenderize the fiber of the ramie fabric for a short time at room temperature to eliminate prickle and improve the softness of the fabric. Scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and thermal gravity analysis (TG) were used to investigate the morphology and structure of treated ramie fabric. And its softness, smoothness, fiber diameter, breaking strength, air permeability, and moisture absorption were also studied. The results showed that the fibers were slenderized, the stiff, coarse hairiness was reduced, and the softness of the fabric was improved, while its other properties remained good after the ramie fabric was treated under appropriate conditions. The use of copper ammonia solution at room temperature to eliminate the prickle of ramie fabrics was simple and inexpensive, suitable for use in practical production.

There are significant incentives/pressures on decreasing the use of plastics and their related products in the packaging industry, correspondingly, strong demands are emerging for clean, renewable, recyclable/ biodegradable packaging products. In this context, molded fiber/pulp products have attracted increasing attention, due to their green/sustainable advantages, simply because the raw materials used are plant-based and/or recycled fibers. Many companies have switched their packing practices from plastics to more environmentally friendly products, such as molded fiber products, which already have had and will continue to have obvious effect on packaging industries. This paper initially provides an overview on the general concept of molded pulp products, and further summarizes the different types of molded fiber products in terms of natural fiber sources, manufacturing processes, current and emerging applications as well as the environmental sustainability of molded products.

BackgroundRhabdomyosarcoma (RMS) is the most common soft tissue tumor in children, and its most common pathological types include embryonal RMS and alveolar RMS. In contrast, spindle cell RMS (SRMS) is a rare type. Moreover, the tongue is a rare primary site of RMS, and infancy is a rare age at onset.Case presentationTwo infants were diagnosed with lingual RMS at 3 and 5 months after birth, respectively, and were admitted to Beijing Children’s Hospital. The pathological type in both cases was SRMS. Both were classified as low-risk and were treated with surgery and chemotherapy. Case 1 was in complete remission at the latest follow-up, and Case 2 had a relapse 10 months after stopping chemotherapy, achieving complete remission after the multimodal treatment of chemotherapy, surgery, and radiotherapy. The venous blood gene test of the two infants did not indicate a pathogenic mutation or a possible pathogenic mutation related to RMS. In Case 1, variants of the CDK4 and BRCA1 genes, both with unknown significance and a possible relation to RMS, were detected. In Case 2, three gene variants of unknown significance that were possibly associated with RMS—TRIP13, APC, and RAD54L—were identified.ConclusionLingual RMS in infants is rare. Its clinical manifestations lack specificity, and early recognition is complex. The success and timing of local treatment are important prognostic factors. Genetic testing may be helpful for the early detection of tumor susceptibility and the estimation of prognosis.

Abstract Background Y‐box binding protein 1 (YB1 or YBX1) plays a critical role in tumorigenesis and cancer progression. However, whether YB1 affects malignant transformation by modulating non‐coding RNAs remains largely unknown. This study aimed to investigate the relationship between YB1 and microRNAs and reveal the underlying mechanism by which YB1 impacts on tumor malignancy via miRNAs‐mediated regulatory network. Methods The biological functions of YB1 in hepatocellular carcinoma (HCC) cells were investigated by cell proliferation, wound healing, and transwell invasion assays. The miRNAs dysregulated by YB1 were screened by microarray analysis in HCC cell lines. The regulation of YB1 on miR‐205 and miR‐200b was determined by quantitative real‐time PCR, dual‐luciferase reporter assay, RNA immunoprecipitation, and pull‐down assay. The relationships of YB1, DGCR8, Dicer, TUT4, and TUT1 were identified by pull‐down and coimmunoprecipitation experiments. The cellular co‐localization of YB1, DGCR8, and Dicer were detected by immunofluorescent staining. The in vivo effect of YB1 on tumor metastasis was determined by injecting MHCC97H cells transduced with YB1 shRNA or shControl via the tail vein in nude BALB/c mice. The expression levels of epithelial to mesenchymal transition markers were detected by immunoblotting and immunohistochemistry assays. Results YB1 promoted HCC cell migration and tumor metastasis by regulating miR‐205/200b‒ZEB1 axis partially in a Snail‐independent manner. YB1 suppressed miR‐205 and miR‐200b maturation by interacting with the microprocessors DGCR8 and Dicer as well as TUT4 and TUT1 via the conserved cold shock domain. Subsequently, the downregulation of miR‐205 and miR‐200b enhanced ZEB1 expression, thus leading to increased cell migration and invasion. Furthermore, statistical analyses on gene expression data from HCC and normal liver tissues showed that YB1 expression was positively associated with ZEB1 expression and remarkably correlated with clinical prognosis. Conclusion This study reveals a previously undescribed mechanism by which YB1 promotes cancer progression by regulating the miR‐205/200b‒ZEB1 axis in HCC cells. Furthermore, these results highlight that YB1 may play biological functions via miRNAs‐mediated gene regulation, and it can serve as a potential therapeutic target in human cancers.

Abstract Background Targeted drugs have greatly improved the therapeutic outcome of non‐small cell lung cancer (NSCLC) patients compared with conventional chemotherapy, whereas about one‐third of patients are so far not suitable for targeted therapy due to lack of known driver oncogenes such as a mutated receptor tyrosine kinase (RTK) genes. In this study, we aimed to identify therapeutic targets for this subgroup of NSCLC patients. Methods We performed genome‐wide CRISPR/Cas9 screens in two NSCLC cell lines carrying wild‐type TP53 and receptor tyrosine kinase (wtTP53‐RTK) genes using a GeCKO v2.0 lentiviral library (containing 123411 sgRNAs and targeting 19050 genes). MAGeCKFlute was used to analyse and identify candidate genes. Genetic perturbation and pharmacological inhibition were used to validate the result in vitro and in vivo. Results The Genome‐wide CRISPR/Cas9 screening identified MDM2 as a potential therapeutic target for wtTP53‐RTK NSCLC. Genetic and pharmacological inhibition of MDM2 reduced cell proliferation and impaired tumour growth in the xenograft model, thus confirming the finding of the CRISPR/Cas9 screening. Moreover, treatment by a selective MDM2 inhibitor RG7388 triggered both cell cycle arrest and apoptosis in several NSCLC cell lines. Additionally, RG7388 and pemetrexed synergistically blocked the cell proliferation and growth of wtTP53‐RTK tumours but had limited effects for other genotypes. Conclusions We identified MDM2 as an essential gene and a potential therapeutic target in wtTP53‐RTK NSCLC via a genome‐wide CRISPR/Cas9 screening. For this subgroup, treatment by RG7388 alone or by its combination with pemetrexed resulted in significant tumour inhibition.

Detection of amplification of the MYCN gene is essential for determining optimal treatment and estimating prognosis of patients with neuroblastoma (NB). DNA FISH with neuroblastoma tissues or patient‐derived bone marrow cells is the standard clinical practice for the detection of MYCN amplification. As tumor cells may often be unavailable, we developed a method to detect MYCN amplification in the plasma of patients with neuroblastoma. Taking single‐copy NAGK DNA as reference, we used real‐time quantitative PCR (qPCR) to determine the MYCN/NAGK ratio in the plasma of 115 patients diagnosed with NB. An increased MYCN/NAGK ratio in the plasma was consistent with MYCN amplification as assessed by DNA FISH. The AUC for a MYCN/NAGK ratio equal to 6.965 was 0.943, with 86% sensitivity and 100% specificity. Beyond the threshold of 6.965, the MYCN/NAGK ratio correlated with a heavier tumor burden. Event‐free and overall survival of two years were significantly shortened in stage 4 patients with a MYCN/NAGK ratio higher than 6.965. Plasma MYCN/NAGK ratios increased in patients with progressive disease and relapse. Thus, we conclude that the determination of the plasma MYCN/NAGK ratio by qPCR is a noninvasive and reproducible method to measure MYCN amplification in patients with NB.

A flexible 3D N-doped reduced graphene oxide (N-RGO)/carbon nanotube (CNT)MnO2 hybrid film was constructed with outstanding supercapacitor, excellent oxygen reduction reaction (ORR) and good sensing performances. The resultant hybrid film possessed large specific capacitances of 418 F g−1 and 209 mF cm−2 in aqueous and solid electrolytes, and outstanding capacitance retentions of 95% and 94% were obtained for both electrolytes after experiencing 5000 cycles. A simple supercapacitor based on the resultant flexible hybrid film was further fabricated with a much smaller time constant τ0 (0.38 s) than that of typical activated-carbon supercapacitors, suggesting a quick response frequency. Moreover, the assembled supercapacitor device showed high energy densities of 45.72 and 92.13 Wh kg−1 and simultaneously sustained large power densities of 12,526 and 15873 W kg−1 under a scan rate of 50 mV s−1 in aqueous and solid electrolytes, respectively. Furthermore, the resultant flexible film showed excellent performance in the ORR and can also be used to assemble a strain sensor with an excellent sensing performance for bending strain.

Abstract Background Glioblastoma multiforme (GBM) is the most common and lethal type of primary brain tumor. More than half of GBMs contain mutation(s) of PTEN/PI3K/AKT, making inhibitors targeting the PI3K pathway very attractive for clinical investigation. However, so far, PI3K/AKT/mTOR inhibitors have not achieved satisfactory therapeutic effects in clinical trials of GBM. In this study, we aimed to develop a high-throughput screening method for high-throughput identification of potential targeted agents that synergize with PI3K inhibitors in GBM. Methods A Sensitivity Index (SI)-based drug combination screening method was established to evaluate the interactions between BKM120, a pan-PI3K inhibitor, and compounds from a library of 606 target-selective inhibitors. Proliferation, colony and 3D spheroid formation assays, western blotting, comet assay, γ-H2AX staining were used to evaluate the anti-glioma effects of the top-ranked candidates. The drug combination effects were analyzed by the Chou-Talalay method. Results Six compounds were successfully identified from the drug screen, including three previously reported compounds that cause synergistic antitumor effects with PI3K/mTOR inhibitors. TH588, an putative MTH1 inhibitor exhibited significant synergy with BKM120 in suppressing the proliferation, colony formation and 3D spheroid formation of GBM cells. Further investigation revealed that both DNA damage and apoptosis were markedly enhanced upon combination treatment with TH588 and BKM120. Finally, activation of PI3K or overexpression of AKT compromised the anti-glioma efficacy of TH588. Conclusions The screening method developed in this study demonstrated its usefulness in the rapid identification of synergistic drug combinations of PI3K inhibitors and targeted agents.

ABSTRACT Importance There is a high incidence of iron deficiency in children worldwide. Notably, however, while iron deficiency is the most common cause of anemia, little is known about the prevalence and different types of iron deficiency in neuroblastoma patients. Objective The aim of the present study was to investigate the prevalence of iron deficiency in patients newly diagnosed with neuroblastoma. Methods A total of 195 newly diagnosed neuroblastoma patients from November 2015 to January 2018 were analyzed retrospectively. The survival analysis was estimated by the Kaplan‐Meier method. Results Of the 195 neuroblastoma patients included in the study, 121 (62.1%) had iron deficiency, 55 (28.2%) had absolute iron deficiency, and 66 (33.9%) had functional iron deficiency. Being aged ≥ 18 months, tumor originating in the abdomen, International Neuroblastoma Risk Group Staging System M, high‐risk neuroblastoma, lactate dehydrogenase ≥ 1500 U/L, neuron‐specific enolase ≥ 100 U/L, unfavorable histologic category, MYCN amplification, chromosome 1p loss, and bone marrow metastasis were associated with significantly higher rates of functional iron deficiency (P < 0.05). Interpretation Functional iron deficiency at the time of initial neuroblastoma diagnosis predicted lower event‐free survival. Long‐term effects of iron supplementation in neuroblastoma patients with different types of iron deficiency need to be further studied.

Production and consumption as a result of human demand for energy are increasing with each passing day as populations grow [...]

We present a novel stereo visual odometry (VO) model that utilizes both optical flow and depth information. While some existing monocular VO methods demonstrate superior performance, they require extra frames or information to initialize the model in order to obtain absolute scale, and they do not take into account moving objects. To address these issues, we have combined optical flow and depth information to estimate ego-motion and proposed a framework for stereo VO using deep neural networks. The model simultaneously generates optical flow and depth information outputs from sequential stereo RGB image pairs, which are then fed into the pose estimation network to achieve final motion estimation. Our experiments have demonstrated that our combination of optical flow and depth information improves the accuracy of camera pose estimation. Our method outperforms existing learning-based and monocular geometry-based methods on the KITTI odometry dataset. Furthermore, we have achieved real-time performance, making our method both effective and efficient.

Previous studies have shown that the pollutants in exhaust gas can cause performance deterioration in air-fuel oxygen sensors. Although the content of Pb in fuel oil is as low as 5 mg/L, the effect of long-term Pb accumulation on TiO2 oxygen sensors is still unclear. In this paper, the influence mechanism of Pb-containing additives in automobile exhaust gas on the response characteristics of TiO2 oxygen sensors was simulated and studied by depositing Pb-containing pollutants on the surface of a TiO2 sensitive film. It was found that the accumulation of Pb changed the surface gas adsorption state and reduced the activation energy of TiO2, thus affecting the steady-state response voltage and response speed of the TiO2-based oxygen sensor.

Abstract Metabolite‐protein interactions (MPIs) play key roles in cancer metabolism. However, our current knowledge about MPIs in cancers remains limited due to the complexity of cancer cells. Herein, the authors construct an integrative MPI network and propose a MPI network based hepatocellular carcinoma (HCC) subtyping and mechanism exploration workflow. Based on the expressions of hub proteins on the MPI network, two prognosis‐distinctive HCC subtypes are identified. Meanwhile, multiple interdependent features of the poor prognostic subtype are observed, including hypoxia, DNA hypermethylation of metabolic pathways, fatty acid accumulation, immune pathway up‐regulation, and exhausted T‐cell infiltration. Notably, the immune pathway up‐regulation is probably induced by accumulated unsaturated fatty acids which are predicted to interact with multiple immune regulators like SRC and TGFB1. Moreover, based on tumor microenvironment compositions, the poor prognostic subtype is further divided into two sub‐populations showing remarkable differences in metabolism. The subtyping shows a strong consistency across multiple HCC cohorts including early‐stage HCC. Overall, the authors redefine robust HCC prognosis subtypes and identify potential MPIs linking metabolism to immune regulations, thus promoting understanding and clinical applications about HCC metabolism heterogeneity.

Abstract Background Neuroblastoma is the most common extracranial solid tumor of childhood. The high rate of recurrence is associated with a low survival rate for patients with high-risk neuroblastoma. There is thus an urgent need to identify effective predictive biomarkers of disease recurrence. Methods A total of 116 patients with high-risk neuroblastoma were recruited at Beijing Children’s Hospital between February 2015 and December 2017. All patients received multidisciplinary treatment, were evaluated for the therapeutic response, and then initiated on maintenance treatment. Blood samples were collected at the beginning of maintenance treatment, every 3 months thereafter, and at the time of disease recurrence. Plasma levels of cell-free DNA (cfDNA) were quantified by qPCR. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the ability of plasma cfDNA concentration to predict recurrence. Results Of the 116 patients, 36 (31.0%) developed recurrence during maintenance treatment. The median time to recurrence was 19.00, 9.00, and 8.00 months for patients who had achieved complete response (n = 6), partial response (n = 25), and stable disease (n = 5), respectively, after multidisciplinary treatment. The median plasma cfDNA concentration at the time of recurrence was significantly higher than the concentration in recurrence-free patients throughout maintenance treatment (29.34 ng/mL vs 10.32 ng/mL). Patients recorded a plasma cfDNA level ≥ 29 ng/mL an average of 0.55 months before diagnosis of disease recurrence. ROC analysis of the power of plasma cfDNA to distinguish between patients with or without recurrence yielded an area under the curve of 0.825, with optimal sensitivity and specificity of 80.6 and 71.3%, respectively, at a cfDNA level of 12.93 ng/mL. Conclusions High plasma cfDNA concentration is a potential molecular marker to signal disease recurrence in patients with high-risk neuroblastoma.

The uncertainties from renewable energy sources (RESs) will not only introduce significant influences to active power dispatch, but also bring great challenges to the analysis of optimal reactive power dispatch (ORPD). To address the influence of high penetration of RES integrated into active distribution networks, a distributionally robust chance constraint (DRCC)-based ORPD model considering discrete reactive power compensators is proposed in this paper. The proposed ORPD model combines a second-order cone programming (SOCP)-based model at the nominal operation mode and a linear power flow (LPF) model to reflect the system response under certainties. Then, a distributionally robust optimization (WDRO) method with Wasserstein distance is utilized to solve the proposed DRCC-based ORPD model. The WDRO method is data-driven due to the reason that the ambiguity set is constructed by the available historical data without any assumption on the specific probability distribution of the uncertainties. And the more data is available, the smaller the ambiguity would be. Numerical results on IEEE 30-bus and 123-bus systems and comparisons with the other three-benchmark approaches demonstrate the accuracy and effectiveness of the proposed model and method.

Abstract Background To improve cure rates for neuroblastoma (NB), it is important and necessary to evaluate therapy response. Our investigation focuses on using plasma cell free DNA (cfDNA) as a biomarker to determine tumor burden and minimal residual disease (MRD) of NB patients during chemotherapy. Methods Total 58 NB patients were recruited from July 2016 to December 2017. Therapy regime and risk classification were based on COG standard and BCH‐NB‐2007 protocol. RECIST study was used to judge response to therapy at the end of fourth cycle of chemotherapy (CC4) and maintenance stage (MS) respectively. Serial quantifications of cfDNA, NSE, and LDH were examined at four stages, including newly diagnosed, second and CC4, and maintenance. Results During early chemotherapy, 65.5% of NB kids responded well. Consistently, cfDNA, NSE, and LDH levels were down‐regulated in NB patients with partial remission (PR) compared to those with stable disease (SD). In both training and predicting sets, the levels of cfDNA were significantly comparable between PR and SD only at CC4 stage. To predict the insufficient response to early chemotherapy, the optimal AUC value of cfDNA was 0.732 and 0.747 in training and predicting sets respectively, with a sensitivity of 63.2% and 80% specificity at 11.59 ng/ml and a sensitivity of 68.4% and 90% specificity at 10.35 ng/ml. At MS, responded NB patients were slightly increased up to 70%. This evaluation was confirmed by further decrease in cfDNA and NSE levels during intermediate chemotherapy in comparison with early stage. Conclusion The dynamic change of cfDNA was considered as a surrogate biomarker to evaluate tumor burden and MRD of NB during early and intermediate therapy periods.

Chitosan nanoparticles (NPs) exhibit great potential in drug-controlled release systems. A controlled hydrodynamic cavitation (HC) technique was developed to intensify the emulsion crosslinking process for the synthesis of chitosan NPs. Experiments were performed using a circular venturi and under varying operating conditions, i.e., types of oil, addition mode of glutaraldehyde (Glu) solution, inlet pressure (Pin), and rheological properties of chitosan solution. Palm oil was more appropriate for use as the oil phase for the HC-intensified process than the other oil types. The addition mode of water-in-oil (W/O) emulsion containing Glu (with Span 80) was more favorable than the other modes for obtaining a narrow distribution of chitosan NPs. The minimum size of NPs with polydispersity index of 0.342 was 286.5 nm, and the maximum production yield (Py) could reach 47.26%. A positive correlation was found between the size of NPs and the droplet size of W/O emulsion containing chitosan at increasing Pin. Particle size, size distribution, and the formation of NPs were greatly dependent on the rheological properties of the chitosan solution. Fourier transform infrared spectroscopy (FTIR) analysis indicated that the molecular structure of palm oil was unaffected by HC-induced effects. Compared with ultrasonic horn, stirring-based, and conventional drop-by-drop processes, the application of HC to intensify the emulsion crosslinking process allowed the preparation of a finer and a narrower distribution of chitosan NPs in a more energy-efficient manner. The novel route developed in this work is a viable option for chitosan NP synthesis.

As a kind of green renewable resource from trees, wood has abundant porous structure, which makes it have great potential in the field of energy storage. However, poor conductivity and limited energy storage capacity hinder the application of wood in the field of energy storage. Here, a novel carbonization lignin-free wood (CLFW)@Co-CoS hybrid is designed and fabricated by a combination of vacuum filtration and carbonization. The CLFW@Co-CoS hybrid assembled into wood-based supercapacitor presents a high areal energy density of 610 μWh cm−2, meanwhile maintaining a high areal power density of 192 mW cm−2. There are two main reasons for the excellent capacitance characteristics: one thing is that wood has a natural and abundant porous structure, which provides more space and channels for the storage and transport of electrolyte ions. The other thing is that CoS and Co can provide high capacitance, and numerous new pores are created by the interweaving of CoS nanofibers with flower-like structure. Additionally, Co nanoparticles attached to CoS and wood have more active sites, which endows the hybrid with excellent ORR properties. Thus, this bifunctional material with excellent electrochemical performance and outstanding ORR properties has huge potential in the field of energy storage and catalysis.

Chitosan, derived from chitin, a major constituent (in quantity) of crustaceans, is a unique aminopolysaccharide with emerging commercial potential in agriculture, food, pharmaceuticals and nutraceuticals due to its nontoxic, biodegradable and biocompatable properties. Chitosan coating on fruits and vegetables has been found to be effective for the reduction of a variety of harmful micro-organims and extend the shelf-life of these products. In this review, our focus is on the antimicrobial properties of chitosan and its application as a natural preservative for fresh products. We detailed the key properties that are related to food preservation, the molecular mechanism of the antimicrobial activity of chitosan on fungi, gram-positive and gram-negative bacteria, coating methods for using chitosan and its formulation for preserving fruits and vegetables, as well as the radiation method of producing chitosan from chitin. Understanding the economic and scientific factors of chitosan’s production and efficiency as a preservative will open its practical application for fruits and vegetable preservation.

During the COVID-19 pandemic, many general hospitals have been transformed into designated infectious disease care facilities, where a large number of patients with COVID-19 infections have been treated and discharged. With declines in the number of hospitalizations, a major question for our healthcare systems, especially for these designated facilities, is how to safely resume hospital function after these patients have been discharged. Here, we take a designated COVID-19-care facility in Wuhan, China, as an example to share our experience in resuming hospital function while ensuring the safety of patients and medical workers. After more than 1200 patients with COVID-19 infections were discharged in late March, 2020, our hospital resumed function by setting up a three-level hospital infection management system with four grades of risk of exposure. Moreover, we also took measures to ensure the safety of medical personnel in different departments including clinics, wards, and operation rooms. After all patients with COVID-19 infections were discharged, during the five months of regular function from April to September in 2020, no positive cases have been found among more than 40,000 people in our hospital, including hospital staff and patients.

Abstract To evaluate plasma cell‐free DNA (cfDNA) as a promising biomarker for neuroblastoma (NB) tumor burden. Seventy‐nine eligible patients with newly diagnosed NB were recruited from Beijing Children's Hospital between April 2016 and April 2017. Additionally, from September 2011 to June 2017, 79 patients with stable NB were evaluated with a median follow‐up time of 21 months. Approximately 2 mL of peripheral blood was drawn upon enrollment, and plasma cfDNA levels were measured via quantitative polymerase chain reaction (qPCR). Total cfDNA analysis was performed using the long interspersed nuclear element 1 (LINE‐1) 79 bp fragment, and DNA integrity was calculated by the ratio of the LINE‐1 300 bp fragment to the LINE‐1 79 bp fragment. A total of 79 NB patients with a median age of 36 months comprised the group of newly diagnosed NB patients. The main primary tumor site was the retroperitoneal and adrenal region (81%). Three or more metastatic sites were found in 17.7% of patients. Stable NB patients older than 18 months comprised 98.7% of the stable NB patients. Neuron‐specific enolase (NSE), lactate dehydrogenase (LDH), and cfDNA levels were dramatically increased in the newly diagnosed NB patients and significantly different from those in the stable NB patients. Moreover, the concentration of cfDNA was much higher in patients with larger tumors. By analyzing the area under the receiver operator characteristic (ROC) curve (AUC), the areas of total cfDNA, NSE, and LDH levels were 0.953, 0.929, and 0.906, respectively. The sensitivity and specificity data clarified that the level of circulating cfDNA in plasma can be considered as a reliable biomarker for describing tumor load in NB. The plasma cfDNA concentration was as good as the levels of LDH and NSE to discriminate the tumor burden in children with NB.

Abstract Background We ought to explore the acquired somatic alterations, shedding light on genetic basis of somatic alterations in NB patients with chemotherapy. Methods Marrow blood samples from NB patients were collected before treatment, after the 2nd and 4th chemotherapy for baseline research and continuous monitoring by whole exome sequencing. Plasma cell free DNA (cfDNA) was prepared for baseline research. Finger nail cells were extracted as self control. The clinical data was analyzed. Results From December 2014 to February 2016, 27 cases of children with stage IV NB were diagnosed. The follow up time ranged from 5 to 25 months, with a median follow up time of 17 months, 20 patients were stable, one patient died of pulmonary embolism during surgery, six patients died of disease progression. Marrow blood whole exome sequencing demonstrated that several novel somatic mutations were identified in all three trios comply or against the trendy of tumor size variation. Of note, six recurrent mutations in bromodomain PHD finger transcription factor (BPTF) were identified in nine NB patients under the continuous monitoring. The mutation rates variation was positively correlated to tumor size (CC = 0.428, P = 0.021), and patients with BPTF mutation may have a worse prognosis compared with wild type. Meanwhile, CGREF1, CUX2, GP1BA, SLC45A1 and TRA2A were mutated with the trendy oppose as therapeutic effects. The baseline research in three NB patients demonstrated that mutation rate of BPTF, TMCO3, GPRIN2 and C20orf96 in plasma cfDNA were in positive correlation with bone marrow genomic DNA (P = 0.001). Conclusions Our study showed that BPTF along with other mutations may function as a biomarker for evaluating to effects of chemotherapy to this refractory tumor, and patients with BPTF mutation might have a worse prognosis.

Background: The pro-inflammatory cytokine, interleukin-6 (IL-6), stimulates the metastasis of several neoplasms. An association of its serum level and the single nucleotide polymorphism (SNP) rs1800795 with neuroblastoma (NB) has been reported in American and Italian cohorts. This study was to clarify whether the same association exists in Chinese children. Methods: A total of 130 NB patients, with 77 boys (59%), 53 girls (41%), mean age 41 ± 5 months, were assigned to two groups: high risk (HR) versus intermediate-low risk (non-HR), and 50 healthy children were randomly selected as the age- and gender-matched controls. Peripheral blood samples were analyzed to determine serum IL-6 level using enzyme linked immunosorbent assay and rs1800795 SNPs phenotype using polymerase chain reaction and gene sequencing. Results: There were 87 NB patients in the HR group and 43 NB patients in the non-HR group. A comparison of allele and genotype frequencies of the rs1800795 polymorphism between patients and controls found no association with NB risk (P > 0.05). The frequency of GG+GC genotype was higher in HR-NB patients than in non-HR-NB patients (64.4% vs. 48.8%, P = 0.02), and serum IL-6 level was much higher in HR-NB patients with GG+GC genotype than in HR-NB patients with CC genotype (4.36 ± 1.1 pg/ml vs. 1.83 ± 0.5 pg/ml; P = 0.02), but not in Non-HR-NB patients. Conclusions: The polymorphism rs1800795 is associated with serum IL-6 level and level of NB risk. GG genotype might indicate that the tumor is highly malignant (prone to metastasis) and associated with poor prognosis.

[This corrects the article DOI: 10.1371/journal.pone.0103482.].

Bamboo is one of the most important non-wood raw materials for the pulp and paper industry in Asia and particularly in China. However, its high silicon content can cause challenges in the pulping and alkali recovery systems. Further understanding of the distribution, morphology, and composition of silicon in bamboo culm will be beneficial in solving these challenges. In this study, modern analytical tools such as scanning electron microscopy (SEM) and scanning electron microscopy equipped with an energy dispersive X-ray (SEM-EDX) were used to characterize the distribution, morphology, and composition of silicon in the bamboo culm. The results showed that silicon is mainly distributed in the outer skin and inner skin. The silicon deposits exist in a number of shapes, and sinuate is the most common one. Their sizes range from about 0.15 μm to 0.9 μm in the cell wall and between 0.3 μm to 1.5 μm in the cell lumen. Localized silicon deposits are present in the forms of its oxide, silica, monatomic silicon, and/or organosilicon. Based on the above results, two potential techniques are recommended for pulp mills to minimize silicon-related challenges.

The increasing consumption of regenerated cellulose, in particular the viscose fiber, has led to a significant development of dissolving pulps in the last decade. In this review paper, the current status of dissolving pulp with respects to raw materials, manufacturing processes, and some key issues are discussed. Non-wood materials and the process concept of upgrading paper-grade pulp into dissolving pulp are also included. Some recent developments related to the analytical methods of the purity and molecular weight distribution based on the ion chromatography and gel permeation chromatography are discussed. Finally, further processing improvements of purification, such as mechanical, chemical, and enzymatic treatment, and their combinations during the manufacturing process of dissolving pulp, are included.

The electrification of loader designs can utilise several power motor types. Hence, this study investigates the operational performance of pure electric-powered loaders matched with three types of motors. Firstly, for the ZL08 loader, it is proposed that a pure electric-powered loader structure adopts two motors to drive the walking and hydraulic systems separately. Secondly, the dynamic parameters of the two motors were matched, and then, a joint vehicle dynamics model of the control system, the Multi-Body Dynamics (MBD) module and the material Discrete Element Method (DEM) module, was established. Finally, the performance of the walking system with three motors was tested by inserting three materials and using accelerating and climbing methods. The operating performance of the hydraulic system was tested by shovelling and unloading three materials. Results show that when inserting difficult materials, the loader’s walking system with switched reluctance motors is 9.74–21.2% deeper than that with the other two motors and 11.7–56.2% faster at the same depth. The hydraulic system consumes 3–15.7% less energy when matched with a permanent magnet synchronous motor than the other two motors. Pure electric loaders have the best operating performance when the walking system is matched with a switched reluctance motor, and the hydraulic system is matched with a permanent magnet synchronous motor.

Grouting reinforcement is an important method used to solve problems encountered during tunnel construction, such as collapse and water gushing. The grouting diffusion process is greatly influenced by the structural characteristics of the fractures in a rock mass. First, an analytical grouting diffusion model of a single rough fracture under constant-pressure control is established based on the constitutive equation of a Bingham fluid. Second, the “quasi-elliptical” grouting diffusion pattern under the influence of roughness is revealed through a grouting diffusion experiment, which is conducted with an independently developed visualized testing apparatus. Furthermore, the analytical formula of roughness-corrected grouting diffusion characterized by the saw tooth density is established. Finally, an elaborate numerical simulation of the diffusion process of cement slurry (Bingham flow type) in a single rough fracture is carried out by introducing the Bingham–Papanastasiou rheological model. The temporal and spatial distribution characteristics of the velocity field and pressure field during the grouting diffusion process are analyzed as well. Moreover, the method and range of the roughness correction factor in the analytical grouting diffusion model are proposed based on the fracture roughness unit.

Background: SIRT1, which belongs to the Sirtuin family of NAD-dependent enzymes, plays diverse roles in aging, metabolism, and disease biology. It could regulate cell survival and has been shown to be a protective factor in heart function. Hence, we verified the mechanism by which SIRT1 regulates doxorubicin induced cardiomyocyte injury in vivo and in vitro. Methods: We analyzed SIRT1 expression in doxorubicin-induced neonatal rat cardiomyocyte injury model and adult mouse heart failure model. SIRT1 was over-expressed in cultured neonatal rat cardiomyocyte by adenovirus mediated gene transfer. SIRT1 agonist resveratrol was used to treat the doxorubicin-induced heart failure mouse model. Echocardiography, reactive oxygen species (ROS) production, TUNEL, qRT-PCR, and Western blotting were performed to analyze cell survival, oxidative stress, and inflammatory signal pathways in cardiomyocytes. Results: SIRT1 expression was down-regulated in doxorubicin induced cardiomocyte injury, accompanied by elevated oxidative stress and cell apoptosis. SIRT1 over-expression reduced doxorubicin induced cardiomyocyte apoptosis with the attenuated ROS production. SIRT1 also reduced cell apoptosis by inhibition of p38MAPK phosphorylation and caspase-3 activation. The SIRT1 agonist resveratrol was able to prevent doxorubicin-induced heart function loss. Moreover, the SIRT1 inhibitor niacinamide could reverse SIRT1's protective effect in cultured neonatal rat cardiomyocytes. Conclusions: These results support the role of SIRT1 as an important regulator of cardiomyocyte apoptosis during doxorubicin-induced heart injury, which may represent a potential therapeutic target for doxorubicin-induced cardiomyopathy.

Galectin-3 has a relatively high level of expression in triple-negative breast cancers and is a potential marker for this disease. However, the clinical and prognostic implications of galectin-3 expression in breast cancer remain unclear. We examined mastectomy specimens from 1086 breast cancer cases and matching, adjacent non-cancerous tissues using immunohistochemistry. Overall, triple-negative breast cancers expressed galectin-3 more strongly than did other breast cancers types (63.59% vs 21.36%, P = 0.001). Galectin-3 expression was not found to be an independent prognostic factor for breast cancer by Cox regression analysis, but was associated with chemotherapeutic resistance. Apoptosis was only weakly induced by arsenic trioxide (ATO) treatment in galectin-3-positive breast cancer cells (MDA-MB-231 and MCF-7), although ATO treatment up-regulated galectin-3 expression. Knockdown of galectin-3 in MDA-MB-231 cells sensitized them to killing by ATO. These findings support a possible role for galectin-3 as a marker for triple-negative breast cancer progression and as a therapeutic target in combination with ATO treatment, although the mechanisms that underlie this synergy require further investigation.